The use of magnetic nanoparticle therapy has promise as a cell specific/high therapeutic ratio, low-toxicity cancer therapy. The most attractive feature of mNP-AMF cancer therapy is the ability to deliver mNP to individual cancer cells via peptide targeting and to selectively kill such cells by exciting the mNPs with a noninvasive/ safe alternating magnetic field (AMF). Project 3 will perform a variety of fundamental studies required to support planned clinical trials for breast cancer using mNP-AMF therapy at Dartmouth. Our preliminary data demonstrate the ability to completely control murine breast tumors with mNP-AMF therapy. Aim 1 investigates performance impact of a variety of mNP variables including, size, delivery route, and antibody targeting, both in vitro in breast cancer cell lines and in vivo with the same cells in syngeneic or xenogeneic grafts in mice. Aim 2 exploits our preliminary data suggesting a reduction of interstitial tumor pressure improves nanoparticle delivery and biodistribution in tumors and investigates the in vivo impact of such reduction. mNP-AMF can among other potential effects generate local hyperthermia and mild hyperthermia is well documented in vitro, in animals and patients to significantly increase the effectiveness of conventional cancer treatment modalities such as radiation and chemotherapy. Aim 3 investigates the synergy between mNP-AMF and radiation or chemotherapy. Aim 4 is designed to directly support the planned clinical trials of mNP-AMF therapy for breast cancer at Dartmouth. Our preliminary experiments have allowed us to define appropriate parameters for mNP-AMF treatment for mice. While extremely useful, this information will not translate directly to human patients. Aim 4 will use human breast and tumor phantoms and an in vivo porcine breast model (we have the appropriate generator and coils) to determine optimal mNP and AMF delivery techniques for the human breast cancer patient. Project 3 will interact with all other projects and cores. The nanoparticle core will supply particles, as will project 1. Projects 1 and 2 will use the models generated by project 3. Project 4 will use the AMF equipment housed in project 3 and interact intellectually with project 3 since each both are using mNP-AMF for therapy. Pathology, Toxicology and Biodistribution core will analyze mNP biodistribution and the Bioinformatics, Statistics and Data Analysis core will perform data analysis and support experimental design.